© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Combined phospholamban ablation and SERCA1a overexpression result in a new hyperdynamic cardiac state
aDepartment of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA
bDepartment of Molecular and Cellular Physiology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267-0575, USA
cDepartment of Physiology and Cell Biology, Ohio State University, Columbus, OH 43210, USA
litsa.kranias{at}uc.edu
* Corresponding author. Tel.: +1-513-558-2377; fax: +1-513-558-2269
Objective: Phospholamban ablation or ectopic expression of SERCA1a in the heart results in significant increases in cardiac contractile parameters. The aim of the present study was to determine whether a combination of these two genetic manipulations may lead to further augmentation of cardiac function. Methods: Transgenic mice with cardiac specific overexpression of SERCA1a were mated with phospholamban deficient mice to generate a model with SERCA1a overexpression in the phospholamban null background (SERCA1OE/PLBKO). The cardiac phenotype was characterized using quantitative immunoblotting, sarcoplasmic reticulum calcium uptake and single myocyte mechanics and calcium kinetics. Results: Quantitative immunoblotting revealed an increase of 1.8-fold in total SERCA level, while SERCA2 was decreased to 50% of wild types. Isolated myocytes indicated increases in the maximal rates of contraction by 195 and 125%, the maximal rates of relaxation by 200 and 124%, while the time for 80% decay of the Ca2+-transient was decreased to 43 and 75%, in SERCA1OE/PLBKO hearts, compared to SERCA1a overexpressors and phospholamban knockouts, respectively. These mechanical alterations reflected parallel alterations in Vmax and EC50 for Ca2+ of the sarcoplasmic reticulum Ca2+ transport system. Furthermore, there were no significant cardiac histological or pathological alterations, and the myocyte contractile parameters remained enhanced, up to 12 months of age. Conclusions: These findings suggest that a combination of SERCA1a overexpression and phospholamban ablation results in further enhancement of myocyte contractility over each individual alteration.
KEYWORDS Ca-pump; Contractile function; Myocytes; SR (function)
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